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Neuron. 2017 Apr 5;94(1):108-124.e7. doi: 10.1016/j.neuron.2017.02.046. Epub 2017 Mar 23.

Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31.

Author information

1
Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University (TMDU), Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan; Center for Brain Integration Research (CBIR), Tokyo Medical and Dental University (TMDU), Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
2
Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University (TMDU), Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan; Center for Brain Integration Research (CBIR), Tokyo Medical and Dental University (TMDU), Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan.
3
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
4
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
5
Institut de Génétique et de Biologie Moléculaire et Cellulaire, University of Strasbourg, Illkirch 67400, France.
6
Research Institute of Biomolecule Metrology, 807-133 Enokido, Tsukuba, Ibaraki 305-0853, Japan.
7
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Yokohama, Kanagawa 223-8522, Japan.
8
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada; Department of Genetics, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
9
Department of Genetics, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Program of Molecular Genetics, University of Toronto, Toronto, ON M5G 0A4, Canada.
10
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
11
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: nagai@neurother.med.osaka-u.ac.jp.
12
Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University (TMDU), Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan; Center for Brain Integration Research (CBIR), Tokyo Medical and Dental University (TMDU), Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan; Center for Personalized Medicine for Healthy Aging, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan. Electronic address: pico.nuro@tmd.ac.jp.

Abstract

Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp. These RBPs suppress UGGAAexp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAAexp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies.

KEYWORDS:

ALS; Drosophila melanogaster; RAN translation; RNA chaperone; RNA foci; SCA31; TDP-43; microsatellite repeat expansion diseases; ribonucleoprotein

PMID:
28343865
PMCID:
PMC5681996
DOI:
10.1016/j.neuron.2017.02.046
[Indexed for MEDLINE]
Free PMC Article

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